TESTIMONY
U.S. House of Representatives
Committee on Government Reform
Subcommittee on National Security, Veterans Affairs, and International Relations
Hearing on
Biological Warfare Defense Vaccine Research & Development Programs
10:00 A.M. - 2:00 P.M.
October 23, 2001
Rayburn House Office Building
Room 2154

Mr. Chairman and Members of the subcommittee: I am very grateful for the opportunity to testify today. I plan to provide a brief overview of some of the advances in vaccine technology that we are developing and which, in one case, has been licensed to a Department of Defense contractor. It is my belief that the scientific advances of recent years can, with the cooperation of government agencies, be rapidly developed and brought to the service of the nation in achieving a much broader, safer, and more flexible arsenal of vaccines to enhance biosecurity.

Prevention is better than cure
It is clear from the current spate of anthrax threats and scares that there is an important place for antibiotics, especially if taken quickly, and in the future this usefulness will continue, as may a role for antidotes and other post-exposure treatments. In addition to logistical difficulties and other drawbacks associated with providing antibiotics to an exposed population is the concern that it would be straightforward for an attacker to produce a strain of multi-drug resistant anthrax. In addition to the same logistical problems, the antidote approach must contend with the fact that the organism that causes anthrax, Bacillus anthracis, is in itself not the cause of illness or death, but rather the producer of toxins that ultimately kill its host or rapidly trigger downstream havoc in the body. AVANT's approach has been to develop vaccines that would prevent the establishment of virulence and subsequent toxin production if the bacteria were to be encountered through any of the known routes: inhalation, ingestion or skin contact.

Anthrax Vaccine Technologies

BioPort

DynPort

AVANT's Vaccine Vectors

Subunit vaccine [Sterile filtrates of B. anthracis culture]

Subunit vaccine that is purer and (theoretically) safer than BioPort vaccine

Live attenuated vaccine - PA vectored in proprietary attenuated Vibrio or Salmonella species

Injectable

Injectable

Oral

6 doses over 18 months to confer complete protection

May require multiple doses to confer protection

Has shown single-dose, protection against cholera

Delayed onset of protection

Probable delayed onset of protection

Rapid protection

The profile of AVANT's vaccines for this market is necessarily one that is user-friendly and rapidly protecting, eliciting protection in a matter of days rather than months. AVANT is currently focused on its core business of protecting travelers. However, the approach is also highly applicable to military uses. Troops could be rapidly protected with all the benefits of systemic and mucosal immunity without enduring multiple painful injections.

AVANT's programs addressing the travelers vaccine market include manufacturing for late-stage clinical trials of single-dose, oral vaccines. We intend to take the travelers vaccines program as a launching pad for the development of potent, single-dose, oral vaccines that should protect rapidly against biowarfare agents.

AVANT's Vaccine Vectors to Counter Bio-terrorism
The use of Vibrio cholerae as a live, attenuated vaccine (CholeraGarde™) and as a vector (VibrioVec™) is extremely attractive because the bacterium is non-invasive and rapidly elicits a prominent and long-lasting immune response after a single, oral dose. Clinical studies using clinical-grade vaccine produced at the Walter Reed Army Institute of Research (WRAIR) Forest Glen facility have been conducted under a NIH sponsored Investigational New Drug (IND) application under the direction of Dr. Mitchell Cohen of Children's Hospital in Cincinnati. Thus far, AVANT's cholera vaccine (CholeraGarde™), based on the Peru-15 strain, has been clinically evaluated in over 120 volunteers including a Phase IIb study in which it was well-tolerated, highly immunogenic, and conferred 100% protection against moderate to severe diarrhea following virulent cholera challenge. AVANT is developing CholeraGarde™ as a travelers' vaccine for cholera and is currently producing cGMP (clinical good manufacturing practice) material for pivotal studies.

Live attenuated VibrioVec™ strains have been evaluated pre-clinically as bacterial vectors of assorted heterologous antigens including shiga-like toxin B-subunit (Slt-B), cholera toxin B subunit (CT-B) fused to an E. histolytica peptide (SREHP) and Shigella sonnei O-antigen. Each vector induced an immune response against the heterologous antigen when administered to mice or rabbits. AVANT is developing the VibrioVec™ vectored S. sonnei O-antigen as a vaccine against dysentery.

It is therefore anticipated that vaccinees immunized with VibrioVec™ vectored protective antigens associated with biological threats (e.g. anthrax or plague) would rapidly become protected from these pathogens.

AVANT's technology allows the vectoring of Protective Antigen (PA) derived from B. anthracis in VibrioVec™ to produce a single-dose, live attenuated vaccine against anthrax. Candidate vaccines will be evaluated preclinically for immunogenicity and protection from toxin challenge in the established germ-free mouse model. With the selection of a suitable strain, cell banking and GMP process development will proceed modeled on current manufacturing practices for CholeraGarde™. The VibrioVec™ vector could provide a platform for the development of a variety of vaccines against bacterial biowarfare agents.

AVANT is also developing other proprietary live bacterial vectors including attenuated Salmonella typhi and S. typhimurium strains. These vectors, deleted at phoP/Q genes that govern virulence, are actively being evaluated both pre-clinically and clinically for their capacity to provoke immune responses against heterologous bacterial and viral antigens. Although less developed, Salmonella derived vectors could provide a platform for delivery of viral antigens to combat viral biowarfare agents.

Conclusion

Advances in vaccine technology, including those currently under development by AVANT, will allow us to expand and improve the vaccine arsenal to offer safer, more effective, and more practical vaccine protection against a wide variety of agents that might be employed by those wishing to attack the civilian population and military forces of the United States.